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[EDITED] YEAR 5: Immunopathology PM > Immuno: Autoinflammatory and Autoimmune diseases 1 > Flashcards

Immuno: Autoinflammatory and Autoimmune diseases 1 Flashcards

1
Q

What is the difference between autoinflammatory and autoimmune disease?

A

Autoinflammatory = driven by components of the innate immune system

  • Not characterised by autoantibodies and HLA associations are usually less strong

Autoimmune = driven by components of the adaptive immune system

  • Autoantibodies are found and HLA associations are common

(Breaking of tolerance - aberrant T and B cell response in 1 and 2 lymphoid organs)

Note: mixed pattern diseases involve mutations affecting the innate and adaptive immune system → HLA associations may be present but autoantibodies are NOT usually a feature

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2
Q

Which cells are mainly responsible for:

  1. Autoinflammatory diseases
  2. Autoimmune diseases
A
  1. Autoinflammatory diseases = macrophages and neutrophils (disease is usually localised)
  2. Autoimmune diseases = T and B cells
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3
Q

Inherited DNA sequence is not the only factor affecting protein expression, what are the other factors?

A
  • Genetics – Germline mutations affecting DNA sequence - Alteration in DNA that occurs in germ cells (sperm and ova and progenitors) and will be passed on to offspring
  • Genetics – Somatic mutations affecting DNA sequence - Alteration in DNA that occurs in a single body cell after conception, does not affect germ cells and so is not inherited
  • Epigenetics - (Heritable) change in gene expression
    (eg via DNA methylation)
  • MicroRNA (miRNA) - Small, non-coding, single stranded RNA
    targets mRNA and regulate protein production
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4
Q

List examples of monogenic autoinflammatory diseases

A

Familial Mediterranean Fever

TRAPS

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5
Q

List examples of polygenic autoinflammatory diseases

A

Crohn’s

UC

Osteoarthritis

Giant cell arteritis

Takayasu’s

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6
Q

List examples of monogenic autoimmune diseases

A

APECED

IPEX

ALPS

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7
Q

List examples of polygenic autoimmune diseases

A

Rheumatoid arthritis

Myasthenia

Pernicious anaemia

Graves disease

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8
Q

List examples of mixed pattern diseases

A

Ankylosing spondylitis

Psoriatic arthritis

Behcet’s

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9
Q

Mutations in which pathways are implicated in monogenic autoinflammatory disease?

A

Innate immune cell function - abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1

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10
Q

Which protein is upregulated in autoinflammatory diseases caused by gain-of-function mutation in NLRP3?

A

Cryopyrin (aka NLRP3)

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11
Q

Name 3 diseases that are caused by mutation of NLRP3?

A
  • Muckle Wells syndrome
  • Familial cold autoinflammatory syndrome
  • Chronic infantile neurological cutaneous articular syndrome/Neonatal Onset Multisystem inflammatory disorder (NOMID)
  • These are all autosomal dominant

NOTE: other examples of monogenic autoinflammatory conditions: TNF receptor associated periodic syndrome (TNF receptor mutation), Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)

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12
Q

Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?

A

MEFV gene

Encodes pyrin-marenostrin which is ordinarily a negative regulator of the inflammatory pathway → mutation leads to increased inflammation

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13
Q

Describe how the inflammasome complex functions.

A
  1. The pathway is activated by toxins, pathogens and urate crystals
  2. These act via cyropyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
  3. Activation of procaspin 1 results in the production of NFkB, IL-1 and apoptosis
  4. Pyrin-marenostrin is a negative regulator of this pathway
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14
Q

Which mutations can lead to hyperactivity of the inflammasome complex?

A
  • Loss of function of pyrin-marenostrin
  • Gain of function of cryopyrin
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15
Q

What is the inheritance pattern of Familial Mediterranean Fever?

A

Autosomal recessive

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16
Q

Which cells contain pyrin-maronostrin?

A

Neutrophils

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17
Q

Outline the clinical presentation of Familial Mediterranean Fever.

A

Periodic fevers lasting 2-4 days associated with:

  • Abdominal pain (peritonitis)
  • Chest pain (pleurisy, pericarditis)
  • Arthritis
  • Rash
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18
Q

What is a complication of Familial Mediterranean Fever?

A

AA amyloidosis
(due to chronic elevation of serum amyloid A)

This can deposit in the kidneys causing nephrotic syndome and renal failure

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19
Q

What are the investigations of Familial Mediterranean Fever?

A
  • High CRP, high Serum Amyloid A (SAA)
  • Blood sample to specialist genetics laboratory to identify MEFV mutation
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20
Q

Outline the treatment of Familial Mediterranean Fever.

A
  • Colchicine 500µg BD (binds to tubulin and disrupts neutrophil migration and chemokine secretion)
  • 2nd line: blocking cytokines
    • Anakinra - IL-1 receptor blocker
    • Etanercept - TNF-alpha blocker
21
Q

What are two types of pathogenesis in monogenic autoimmune diseases?

A

Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function

  • Abnormality in regulatory T cells (IPEX)
  • Abnormality of lymphocyte apoptosis (ALPS)
22
Q

What does IPEX stand for?

A

Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome

23
Q

What mutation causes IPEX? What is the role of this gene?

A

FoxP3 - required for the development of Treg cells

A lack of Tregs leads to autoantibody formation
- Failure to negatively regulate T cell responses
- Autoreactive B cells -> limited repertoire of autoreactive B cells

24
Q

Which autoimmune conditions are often seen in IPEX?

A

“Diabetes, dermatitis, Diarrhoea”
* Enteropathy
* Diabetes mellitus
* Hypothyroidism
* Dermatitis (Eczema)

25
What does ALPS stand for?
Autoimmune lymphoproliferative syndrome
26
Which mutations cause ALPS?
Mutations in the **FAS pathway** leading to **defects in apoptosis** of lymphocytes This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don't die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)
27
Describe the clinical phenotype of ALPS.
* High lymphocyte count * Large spleen and lymph nodes * Autoimmune disease (usually cytopaenias) * Lymphoma - over time
28
What is the best known chromosomal region that is implicated in Crohn's disease?
IBD1 on chromosome 16
29
Which gene in this region is associated with Crohn's disease? (Chromosome 16)
**NOD2 (aka CARD15)** Abnormalities are associated with increased risk of Crohn's, Blau syndrome and some forms of sarcoidosis
30
Where is NOD2 found and what is its role?
Cytoplasm of myeloid cells Acts as a **microbial sensor** (recognises muramyl dipeptide)
31
Outline the treatment approaches to Crohn's disease
* Corticosteroids * Azathioprine * Anti-TNF-alpha antibodies * Anti-IL 12/23 antibodies
32
What is the strongest genetic association of ankylosing spondylitis?
**HLA-B27** NOTE: othes include IL23R, ERAP1, ANTXR2 and ILR2 90% heritability
33
Where does ankylosing spondylitis tend to manifest?
At sites with high shear forces (i.e. entheses, SI Joint)
34
What are the treatment options for ankylosing spondylitis?
* NSAIDs * Immunosuppression (anti-TNF-alpha and anti-IL17)
35
List the autoimmune diseases associated with the following HLA polymorphisms: 1. DR3 2. DR3/4 3. DR4 4. DR15
1. DR3 * Graves' disease * SLE 2. DR3/4 * Type 1 diabetes mellitus 3. DR4 * Rheumatoid arthritis 4. DR15 * Goodpasture's syndrome
36
Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.
* **PTPN22** - suppresses T cell activation * **CTLA4** - regulates T cell function (expressed by T cells)
37
What are three forms of peripheral tolerance?
* T cell require **costimulation** to become activated (costimulatory molecules are upregulated in infection and inflammation) * **Regulatory** T cells * Immune **privileged** sites
38
Outline the Gel and Coombs effector mechanisms of immunopathology.
Type I: Anaphylactic hypersensitivity - immediate hypersensitivity which is **IgE-mediated** Type II: Cytotoxic hypersensitivity - **antibody** reacts with **cellular antigen** Type III: Immune complex hypersensitivity - **antibody** reacts with **soluble antigen** to form an **immune complex** Type IV: Delayed-type hypersensitivity - **T cell mediated** response **NOTE: autoimmunity is most common with type II hypersensitivity**
39
Effect of Type II Hypersensitivity
* Activate complement * Activate NK cells * Opsonin for phagocytosis
40
List some inflammatory mediates involved in type I responses that are: 1. Pre-formed 2. Synthesised
1. Pre-formed: Histamine, Serotonin, Proteases 2. Synthesised: Leukotrienes, prostaglandins, bradykinin, cytokines
41
Outline the pathophysiology of IgE-mediated type I responses.
IgE binds to a foreign antigen (e.g. pollen) The Fc portion binds to mast cells and basophils leading to degranulation NOTE: this mechanism is implicated in eczema
42
How does antibodies binding to cellular antigens lead to cell death?
Antibody-dependent cellular cytotoxicity: antibodies can **activate complement** (by binding to C1) or bind to **NK cells and macrophages** resulting in phagocytosis
43
What is sometimes considered a type V hypersensitivity reaction?
Antibodies **activate or block cellular receptors** (e.g. Graves' disease, myasthenia gravis)
44
Name the autoantigen in the following diseases: 1. Goodpasture's disease 2. Pemphigus vulgaris 3. Graves' disease 4. Myasthennia gravis
1. Goodpasture's disease = non-collagenous domain of basement membrane collagen IV 2. Pemphigus vulgaris = Epidermal cadherin 3. Graves' disease = TSH receptor 4. Myasthenia gravis = nicotinic acetylcholine receptor
45
What are the consequences of immune complex formation in type III hypersensitivity reactions?
Immune complexes can deposit in blood vessels (especially in the kidneys (nephritis), joints and skin (purpura) They **activate complement and inflammatory cells** through their Fc portion Classic example - SLE
46
What is the autoantigen in: 1. SLE 2. Rheumatoid arthritis
* SLE: DNA, histones, RNP * Rheumatoid arthritis: Fc portion of IgG
47
Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved.
* **Insulin-dependent diabetes mellitus**: pancreatic beta-cell antigen * **Multiple sclerosis**: myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein
48
In Type IV hypersensitivity reactions in autoimmunity, what HLA do CD8 and CD4 T cells bind to?
HLA class I molecules present antigen to CD8 T cells HLA class II molecules present antigen to CD4 T cells

[EDITED] YEAR 5: Immunopathology PM (12 decks)

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